US7563825B1 - Modulation of beta-catenin coactivator interactions to effect stem cell growth or differentiation - Google Patents
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- 0 [1*][W]N1CC[2H]N2B*N([2*])CC21 Chemical compound [1*][W]N1CC[2H]N2B*N([2*])CC21 0.000 description 10
- WGLDISCVHRTAAE-GPFFVNSYSA-N C=CC(C)(C)C.[H][C@@](C)(COC(C)=O)C1=C2[C@@H](O[C@H]3OC(CO)C(O)C(OC(C)=O)C3O)[C@H](O)[C@H](C)[C@]3([H])CC[C@]([H])(COC)/C3=C/[C@@]2(C)[C@@H](O)C1 Chemical compound C=CC(C)(C)C.[H][C@@](C)(COC(C)=O)C1=C2[C@@H](O[C@H]3OC(CO)C(O)C(OC(C)=O)C3O)[C@H](O)[C@H](C)[C@]3([H])CC[C@]([H])(COC)/C3=C/[C@@]2(C)[C@@H](O)C1 WGLDISCVHRTAAE-GPFFVNSYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N CCC(C)=O Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
Definitions
- the present invention relates to compounds and methods for modulating the interaction between ⁇ -catenin or ⁇ -catenin and the coactivator protein CBP, or ⁇ -catenin or ⁇ -catenin and the coactivator protein p300, to promote proliferation/dedifferentiation or differentiation of stem/progenitor cells.
- Stem cells have received significant interest over the last few years due to their potential, under suitable cellular microenvironments, to differentiate and develop into a wide array of cell and tissue types.
- Several important biomedical applications would be enabled by the ability to generate sufficient pools of adult stem cells, including cell replacement therapy, gene therapy, and tissue engineering. According to the National Institutes of Health, the therapeutic use of stem cells will become a cornerstone of medicine within the next two decades:
- the invention relates to compounds and methods for modulating the interaction between ⁇ -catenin (or ⁇ -catenin) and the coactivator proteins CBP and p300 to either promote proliferation/or differentiation of stem/progenitor cells.
- the compounds of the present invention either increase or decrease post-translational modifications (i.e. phosphorylation, acetylation, sulfonylation, glycosylation) of CBP, p300, or ⁇ - or ⁇ -catenin thereby modulating the selection of coactivator usage by catenin.
- post-translational modifications i.e. phosphorylation, acetylation, sulfonylation, glycosylation
- the invention also relates to methods for enhancing the proliferation of mammalian stem cells, by administering to the stem cells an agent that selectively modulates the interaction of ⁇ -catenin with CBP or p300.
- the invention further relates to a method for modulating the interaction of ⁇ -catenin with CBP or p300 in a cell, comprising treating the cell with an agent that affects the post-translational modifications of at least one of CBP or p300 or ⁇ -catenin, thereby selectively modulating the interaction of ⁇ -catenin with CBP or p300, wherein said agent does not directly bind to CBP or p300.
- the agent increases the binding of ⁇ -catenin to CBP.
- the agent decreases the binding of p300 to ⁇ -catenin.
- the agent increases the binding of p300 to ⁇ -catenin, or the agent decreases the binding of CBP to ⁇ -catenin.
- the cell may be treated with the agent of the invention ex vivo and the cell may be a stem cell/progenitor cell.
- the agent is applied topically to a mammal comprising said cell.
- the agent increases the binding of ⁇ -catenin to the amino-terminal 110 amino acids of CBP or decreases the binding of ⁇ -catenin to the amino-terminal 110 amino acids of p300.
- the agent decreases the binding of ⁇ -catenin to the amino-terminal 110 amino acids of p300 by inhibiting the phosphorylation of Ser 89 of p300, such as by a serine protein kinase; the serine protein kinase may be PKC or CaMK. CaMK kinases may phosphorylate different residues in this N-terminal region, for example Ser 89, Ser 24.
- the protein kinase may also be PAR-1 or PAR-4, acting either directly or via a kinase cascade.
- the agent decreases the binding of ⁇ -catenin to the amino-terminal 110 amino acids of p300 by inhibiting the phosphorylation of Ser 89 of p300 by increasing the phosphorylation of Ser 90 of p300, such as by a serine protein kinase; the serine protein kinase may be MAPK or CDK.
- the agent modulates the interaction of Ser 89 phosphorylated p300 with a 14-3-3 protein
- the agent may be an analog of Fusicoccin, wherein the analog of Fusicoccin has the following general formula:
- the invention also relates to a method of modulating the interaction of ⁇ -catenin with CBP or p300 in a cell, wherein the agent modulates the interaction of prolyl isomerase (Pin1) with ⁇ -catenin, CBP or p300; in certain embodiments, the agent increases the association of Pin1 with CBP.
- the agent modulates the interaction of prolyl isomerase (Pin1) with ⁇ -catenin, CBP or p300; in certain embodiments, the agent increases the association of Pin1 with CBP.
- the agent may be incorporated into a biomaterial capable of supporting the growth of a stem cell; the stem cell may be a hematopioetic stem cell.
- the invention also relates to a compound having the following general formula (I) and uses thereof to modulate stem cell proliferation, in particular to enhance proliferation:
- the invention further relates to a method of enhancing the proliferation of a mammalian stem cell, comprising administering to the stem cell an agent that selectively modulates the interaction of ⁇ -catenin with CBP or p300; the agent may increase the binding of ⁇ -catenin to CBP; and the agent may decrease the binding of ⁇ -catenin to p300.
- the administration to the stem cell may be ex vivo, and the stem cells may be hematopoietic stem cells, hair cells, neural stem cells, or pancreatic islet cells.
- FIG. 1 is a schematic representation of TGF/ ⁇ -catenin transcription.
- FIG. 2 is a schematic representation of two possible mechanisms of action of ⁇ -catenin, resulting from alternative interaction with CBP or p300 in the nucleus.
- FIG. 3 illustrates that ICG-001 at 10 ⁇ M concentration induces the differentiation of C2C12 myeloblasts, as compared to differentiation medium or growth medium.
- FIG. 4 illustrates that differentiation of C2C12 myeloblasts is induced by 10 ⁇ M ICG-001 as compared to differentiation medium.
- FIG. 5A illustrates the structure of Fusicoccin A (FC-A).
- FIG. 5B illustrates the structure of Fusicoccin J (FC-J).
- FIG. 5C illustrates the structure of cotylenin A (CN-A).
- Stem cells are responsible for the regeneration and maintenance of tissues by balancing the processes of self-renewal (i.e., making new stem cells) and differentiation (i.e., generating cells committed to terminal differentiation). This balance results from integration of regulatory signals intrinsic to the stem cell, as well as extrinsic signals from the microenvironment. Perturbations in the balance between self-renewal and differentiation may result in disease, either as a result of stem cell depletion (e.g., aplastic anemia) or increased self-renewal (e.g., cancer).
- stem cell depletion e.g., aplastic anemia
- self-renewal e.g., cancer
- HSC hematopoietic stem cell
- CBP and p300 play important roles in HSC self-renewal and differentiation.
- CBP and p300 function as molecular integrators of various transcriptional signals. When recruited to promoters by transcription factors, they function as co-activators of transcription through multiple mechanisms, including chromatin remodeling, acetylation of associated proteins, and recruitment of the basal transcription machinery.
- CBP and p300 are highly homologous on a structural level, with up to 93% identity within certain protein-binding domains (SEQ ID NO:1 and 2). For most functions, the two proteins appear to be functionally redundant.
- mouse genetic loss-of-function studies demonstrated a difference between p300 and CBP function in HSCs: loss of CBP results in defective HSC self-renewal, whereas loss of p300 results in defective hematopoietic differentiation.
- CBP and p300 have been previously shown to interact with many of the known transcription factors shown to be important in HSC regulation (e.g., HoxB4, ⁇ -catenin, Notch, AML-1, MLL). Earlier results suggest that within HSCs there may be transcription factors that are specifically co-activated by CBP that are critical for self-renewal, and others that are preferentially co-activated by p300 that are critically required for differentiation.
- One example of a signaling pathway that seems to utilize CBP and p300 differentially is the Wnt signaling pathway.
- the Wnt signaling pathway has been shown to play a pertinent role in the development and maintenance of various tissues, including blood, intestines, and skin.
- ⁇ -catenin (SEQ ID NO:3) is a vertebrate homolog of Drosophila gene armadillo, which functions in both cell adhesion and, as discussed herein, the Wnt signaling pathway.
- ⁇ -catenin (SEQ ID NO:4) is also a vertebrate homolog of armadillo.
- ⁇ -catenin and ⁇ -catenin have analogous structures and functions, and they have the ability to be regulated by the APC tumor suppressor.
- Activation of the Wnt signaling pathway requires the nuclear stabilization of TCF (T cell actor)/ ⁇ -catenin complexes and recruitment of transcriptional co-activators, such as CBP and p300.
- TCF T cell actor
- ⁇ -catenin is constitutively produced in the cell, and inhibitory mechanisms exist to maintain ⁇ -catenin levels at below those that would lead to aberrant transcriptional activity in vivo, leading to pathological conditions such as cancer.
- Emami and colleagues PNAS101: 12682-7, 2004
- ⁇ -catenin preferentially associates with CBP in cancer cells In one example of aberrant regulation, Emami and colleagues (PNAS101: 12682-7, 2004) recently demonstrated that ⁇ -catenin preferentially associates with CBP in cancer cells.
- ⁇ -catenin when ⁇ -catenin was prevented from associating with CBP, by utilizing a ⁇ -catenin/CBP-specific inhibitor, ⁇ -catenin could bind to p300.
- the “alternative” binding of ⁇ -catenin to p300 was accompanied by the execution of a differentiative genetic program (Teo J et al. PNAS, 102, 2005).
- ⁇ -catenin is thought to promote proliferation without differentiation by binding to and activating CBP, and to initiate differentiation with limited proliferation by binding to and activating p300. Perturbation of ⁇ -catenin interaction with CBP and/or p300 is expected therefore to influence differentiation or proliferation.
- Stem cell therapy is based on the ability of human fetal or adult pluripotent stem cells to differentiate into a variety of cell types. Stem cells may be used to replace damaged cells as a treatment for many different diseases including cancer, Parkinson's disease, spinal cord injury, burns, diabetes, heart disease, rheumatoid arthritis, and osteoarthritis and for gene therapy (Lazic, S E. et al. J Hematother Stem Cell Res, 12(6):635-642, Gafni, Y. et al. Gene Ther. 11(4):417-426). Stem cell therapy has long been an exciting potential medical breakthrough. The ability to inject normal stem cells into a patient, where they could generate organ-specific cells to potentially replace defective patient tissues, offers enormous potential.
- BMT bone marrow transplantation
- PBSCT peripheral blood stem cell transplantation
- UCBSCT umbilical cord blood stem cell transplantation
- a unifying feature of all cancers is their capacity for unlimited self-renewal, which is also a defining characteristic of normal stem cells. Decades ago, it was discovered that the proliferative capacity of all cancer cells was not equivalent, and only a small minority of tumor cells were able to proliferate extensively (Hamburger, A. W. et al. (1977) Science, 197(4302):461-463). This gave rise to the concept that malignant tumors are comprised of Cancer Stem Cells , which have great proliferative potential, as well as another pool of more differentiated cancer cells, with limited proliferative capacity.
- the Wnt/ ⁇ -catenin pathway initiates a signaling cascade critical in both normal development and the initiation and progression of cancer (Giles, R H et al. (2003) Biochim Biophys Acta, 1653(1):1-24; Wodarz, A. et al. (1998) Annu Rev Cell Dev Biol, 14:59-88). Wnt signaling and in particular the nuclear functions of ⁇ -catenin have been shown to be important in the maintenance, proliferation as well as the differentiation of stem cells (Song, X. et al. (2003) Development, 130(14):3259-3268).
- the Wnt/ ⁇ -catenin pathway normally regulates expression of a range of genes involved in promoting both proliferation and differentiation. Activation of the Wnt pathway allows ⁇ -catenin to accumulate in the nucleus, bind to members of the TCF family of transcription factors, and form a transcriptionally active complex, by recruiting either the transcriptional coactivator CBP or its closely related homolog, p300. However, in greater than 85% of colon cancers, mutations in this pathway lead to constitutive activation and expression of target genes, e.g. c-myc, cyclin D1 and survivin, all of which are critical for rapid cell proliferation (Kolligs, F T. et al.
- HSC Hematopoietic Stem Cells
- HSC hematopoietic stem cells
- non-tumorigenic precursor cells e.g. C2C12 myoblasts ( FIGS. 3 , 4 ) and 3T3-L1 preadipocytes.
- the invention is based on the premise that selectively inhibiting or down-modulating the ⁇ -catenin/p300 interaction (i.e. the right side of the pathway, FIG. 2 ) allows for proliferation without differentiation of pluripotent stem cells.
- a preferable agent of the invention is capable of affecting the post-translational modifications of any one of CBP, p300, or ⁇ -catenin, leading to a selective increase of ⁇ -catenin interaction with CBP or a selective decrease of ⁇ -catenin interaction with p300, wherein the agent does not directly bind to CBP or p300.
- the agent increases the binding of ⁇ -catenin to CBP.
- the agent decreases the binding of ⁇ -catenin to p300.
- the overall result biases the B-catenin pathway towards “proliferative/non-differentitive program” of the target cells, which according to the invention are adult stem cells, such as hematopoietic stem cells, neural stem cells, or skin stem cells.
- adult stem cells such as hematopoietic stem cells, neural stem cells, or skin stem cells.
- preferential binding of ⁇ -catenin to CBP is associated with maintaining hematopoietic stem cells in an undifferentiated state wherein they undergo continuous proliferation, resulting in enhanced numbers of undifferentiated cells useful for repopulating the hematopoietic system of a mammal, such as a human, in need of such treatment.
- Agents suitable for use according to the invention can be screened using co-immunoprecipitation methods as described in Emami et al. PNAS101:12682-7, 2004. Briefly, target cells, in this case HSC, are transfected with full-length ⁇ -catenin or with full-length p300. Nuclear lysates are treated with a radiolabeled test agent alone, or with cold test agent. Unbound radiolabeled test agent is removed, and incorporation of the radiolabeled test agent is measured. The results indicate whether the test agent specifically interacts with p300.
- a separate series of experiments can demonstrate inhibition of the interaction of ⁇ -catenin with p300.
- the minimal binding domain of CBP amino acids 1-111
- p300 amino acids 1-111
- SEQ ID NO:3 amino acids 647-781
- ⁇ -catenin is bound to protein A-agarose beads coated with ⁇ -catenin-specific antibody and incubated with either CBP or p300.
- Unbound proteins are removed by washing, then the specific interactions between ⁇ -catenin and p300, and ⁇ -cateninand CBP, are challenged using the test agent, for testing the compounds which directly bind to CBP or phosphor Ser89 p300.
- Agents that either increase the binding of ⁇ -catenin to CBP or decrease the binding of ⁇ -catenin to p300 are further tested in vitro using a suitable model of hematopoietic stem cell proliferation/differentiation.
- a suitable model of hematopoietic stem cell proliferation/differentiation is described in Rebel, V. I. et al., PNAS 99:14789-14794, 2002.
- Agents according to the invention may achieve the desired biological effects through one of several mechanisms.
- the agent may increase the binding of ⁇ -catenin to the amino-terminal 110 amino acids of CBP, or it may decrease the binding of ⁇ -catenin to the amino-terminal 110 amino acids of p300.
- the decrease in binding of ⁇ -catenin to p300 may be achieved by inhibiting the phosphorylation of Ser 89 of p300, wherein the phosphorylation is catalyzed by protein kinase C-epsilon (PKC), calcium/calmodulin-dependent protein kinase (CaMK), LKB (PAR-4), AMP activated kinase (PAR-1), or other serine/threonine protein kinase either directly or indirectly via a kinase cascade.
- PDC protein kinase C-epsilon
- CaMK calcium/calmodulin-dependent protein kinase
- LKB LKB
- PAR-4 AMP activated kinase
- PAR-1 serine/threonine protein kinase either directly or indirectly via a kinase cascade.
- the decreased phosphorylation of Ser 89 of p300 may be achieved by increasing the phosphorylation of Ser 90, for example by mitogen-activated protein kinase 4 (MAPK), cyclin-dependent kinase (CDK), or other serine/threonine protein kinase (eg. PI3K).
- mitogen-activated protein kinase 4 MAPK
- CDK cyclin-dependent kinase
- PI3K serine/threonine protein kinase
- a preferable agent of the invention may modulate the interaction of Ser 89-phosphorylated p300 with 14-3-3 proteins.
- Such agents may be analogs of Fusicoccin, such as Fusicoccin A, Fusicoccin J, and cotylenin A.
- Fusicoccin A, Fusicoccin J, and cotylenin A The structures of Fusicoccin A, Fusicoccin J, and cotylenin A are shown in FIG. 5 .
- Fusicoccin is a fungal toxin that is used to study H+-ATPase activation. The mechanism involves inducing an irreversible bond between the C-terminal portion of H+-ATPase, and 14-3-3 protein. (Svennilid, F.
- the agent modulates the interaction of Pin1 with ⁇ -catenin or with CBP or p300. In one embodiment of the invention, the agent increases the association of Pin1 with ⁇ -Catenin/CBP.
- Pin1 prolyl isomerase
- Pin1 overexpression has been reported to occur in human breast cancer. (Ryo, A. et al., Nat. Cell Biol. 3:793-801 (2001)). Pin1 has also been implicated in normal spermatogenesis. Atchison, F. W. et al. (Biol. Reprod. 69:1989-1997, 2003) reported that adult Pin1-deficient mice exhibited evidence of accelerated exhaustion of stem cell potential, and possible bias towards the differentiation pathway in the absence of Pin1.
- Pin1 specifically recognizes phosphorylated S/T—P bonds (Ser/Thr-Pro motifs). For example, Pin1 directly binds a phosphorylated Ser-Pro motif (Ser 246-Pro) next to the APC-binding site in ⁇ -catenin, inhibits ⁇ -catenin interaction with adenomatous polyposis coli protein (APC), and thereby increases its translocation into the nucleus.
- Ser-Pro motif Ser 246-Pro
- APC adenomatous polyposis coli protein
- Pin1 can also affect coactivator interactions with transcription factors.
- P73 is a transcription factor related to the tumor suppressor p53.
- Pin1-modified p73 displayed a higher affinity for p300 than unmodified p73. (Montovani, F. et al., Mol. Cell. 14:625-636, 2004.)
- Pin1 binding to phosphorylated ⁇ -catenin can increase the ⁇ -catenin/CBP interaction and thereby ⁇ -catenin/CBP dependent gene transcription promoting proliferation at the expense of differentiation.
- the agents of the invention can be incorporated into biomaterials on which hematopoietic stem cells are grown. Examples are disclosed in Horak et al. Biomaterials 25, 5249-60, 2004 and Harrison et al. Biomaterials 25, 4977-86, 2004.
- hematopietic stem cells are disclosed herein as an embodiment of a target for the methods of the invention, the methods are applicable to any adult mammalian stem cells (or ES cells) that can be used for tissue regeneration.
- Adult stem cells constitute an undifferentiated population of cells that retain the ability to proliferate throughout postnatal life and to differentiate into specialized cells to replace cells that become diseased, die or are lost. (Agrawal, S. et al; Trends in Biotechnology 23:78-83, 2005.)
- stem cells suitable for use according to the invention include neural stem cells, skin stem cells, muscle stem cells, and pancreatic islet cells.
- pancreas-derived multipotent precursors Other stem cells may be induced to direct their differentiation toward the ⁇ cell.
- the methods and agents of the invention are suitable for inducing proliferation and limiting differentiation, in order to achieve a suitable number of cells for therapeutic use.
- Adult neural stem cells can differentiate into neurons, astrocytes, and oligodendrocytes, which are the three major lineages of the adult nervous system. For such applications of the invention, it may be appropriate to manipulate adult neural stem cells in situ in order to achieve neurogeneration in vivo.
- Active stem cells exist in adult brain in the dentate gyrus region of the hippocampus and the subventricular zone of the forebrain, and these stem cells can differentiate into neurons, astrocytes and oligodendrocytes.
- quiescent stem cell pools exist in the spinal cord, substantia nigra, optic nerve, and hypothalmus. (Agrawal, S. et al., 2005). Thus, defined pools of neural stem cells are available for modulation according to the invention.
- Skin stem cells may be induced to proliferate in vivo in order to enhance or restore hair growth. Recent evidence suggests that the Wnt pathway is involved in the ability of skin epithelial cells to acquire and/or maintain characteristics of multipotent stem cells. (Alonso, L. et al.; PNAS 100:11830-11835, 2003). Multipotent stem cells in skin receive Wnt signals before they commit to form hair follicles. In transgenic mouse skin in which ⁇ -catenin is constitutively stabilized, adult interfollicular epidermis takes on characteristics of embryonic skin, and may have the capacity to develop into hair follicles. (Gat, V., Cell 95:605-614, 1998).
- agents and methods of the invention are suitable for enhancing the proliferation of multipotent stem cells in the skin, to provide a reservoir of cells capable of forming hair follicles in order to increase or replace lost hair growth, including in vivo applications, for example by topical use.
- U.S. Pat. No. 6,419,913 discloses compositions suitable for topical delivery of therapeutic agents including agents for treatment of hair loss.
- U.S. Pat. No. 6,680,344 also discloses topical delivery of agents for treating hair loss.
- the invention provides methods to enhance the proliferation of mammalian stem cells expressing an exogenous gene, prior to administration of the cells for therapeutic use.
- the gene therapy may also be conducted in vivo, for example, to alter the differentiation potential of neural stem cells.
- OCT4 is a known marker of the undifferentiated stem/progenitor cell state, and the promoter region can be functionally linked to a reporter gene such as EGFP (enhanced green fluorescent protein) as described in Gerrard, L. et al., Stem Cells 23:124-133 (2005), or luciferase.
- EGFP enhanced green fluorescent protein
- Methods for testing the effect of small molecules on stem cells in vitro include those described by Chen, J. K. et al., P.N.A.S. 99:14701-14076 (2002) and Frank-Kamenetsky, M. et al., J. Biol 1:10 (2002).
- Agents for use in the invention include a ⁇ -helix mimetic structure having the following formula (I):
- A is —(C ⁇ O)—(CHR 3 )—
- B is —N—R 4 —
- D is —(CHR 5 )— or —(C ⁇ O)—
- E is —(ZR 6 )— or —(C ⁇ O)—
- G is —(XR 7 ) n —, —(CHR 7 )—(NR 8 )—, —(C ⁇ O)—(XR 9 )—, or —(C ⁇ O)—
- W is —Y(C ⁇ O)—, —(C ⁇ O)NH—, —(SO 2 )— or nothing
- Y is oxygen or sulfur
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of aminoC 2-5 alkyl, guanidineC 2-5 alkyl, C 1-4 alkylguanidinoC 2-5 alkyl, diC 1-4 alkylguanidino-C 2-5 alkyl, amidinoC 2-5 alkyl, C 1-4 alkylamidino C 2-5 alkyl, diC 1-4 alkylamidinoC 2-5 alkyl, C 1-3 alkoxy, Phenyl, substituted phenyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy,
- R 1 , R 2 , R 6 of E, and R 7 , R 8 and R 9 of G are the same or different and represent the remainder of the compound, and R 3 or A, R 4 of B or R 5 of D is selected from an amino acid side chain moiety or derivative thereof.
- the term “remainder of the compound” means any moiety, agent, compound, support, molecule, linker, amino acid, peptide or protein covalently attached to the ⁇ -helix mimetic structure at R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and/or R 9 positions. This term also includes amino acid side chain moieties and derivatives thereof.
- amino acid side chain moiety represents any amino acid side chain moiety present in naturally occurring proteins including (but not limited to) the naturally occurring amino acid side chain moieties identified in Table 1.
- Other naturally occurring amino acid side chain moieties for use in this invention include (but are not limited to) the side chain moieties of 3,5-dibromotyrosine, 3,5-diiodotyrosine, hydroxylysine, ⁇ -carboxyglutamate, phosphotyrosine and phosphoserine.
- glycosylated amino acid side chains may also be used in the practice of this invention, including (but not limited to) glycosylated threonine, serine and asparagine.
- Amino Acid Side Chain Moieties Amino Acid Side Chain Moiety
- amino acid side chain moieties of the present invention also include various derivatives thereof.
- a “derivative” of an amino acid side chain moiety includes modifications and/or variations to naturally occurring amino acid side chain moieties.
- the amino acid side chain moieties of alanine, valine, leucine, isoleucine and pheylalanine may generally be classified as lower chain alkyl, aryl, or arylalkyl moieties.
- Derivatives of amino acid side chain moieties include other straight chain or brached, cyclic or noncyclic, substitutes or unsubstituted, saturated or unsaturated lower chain alkyl, aryl or arylalkyl moieties.
- amino acid side chain derivative is selected from a C 1-12 alkyl, a C 6-12 aryl and a C 7-12 arylalkyl, and in a more preferred embodiment, from a C 1-7 alkyl, a C 6-10 aryl and a C 7-11 arylalkyl.
- Amino side chain derivatives of this invention further include substituted derivatives of lower chain alkyl, aryl, and arylalkyl moieties, wherein the substituents is selected from (but are not limited to) one or more of the following chemical moieties: —OH, —OR, —COOH, —COOR, —CONH 2 , —NH 2 , —NHR, —NRR, —SH, —SR, —SO 2 R, —SO 2 H, —SOR and halogen (including F, Cl, Br and I), wherein each occurrence of R is independently selected from straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated lower chain alkyl, aryl, and aralkyl moieties.
- substituents is selected from (but are not limited to) one or more of the following chemical moieties: —OH, —OR, —COOH, —COOR, —CONH 2
- cyclic lower chain alkyl, aryl and arylalkyl moieties of this invention include naphthalene, as well as heterocyclic compounds such as thiophene, pyrrole, furan, imidazole, oxazole, thiazole, pyrazole, 3-pyrroline, pyrrolidine, pyridine, pyrimidine, purine, quinoline, isoquinoline and carbazole.
- Amino acid side chain derivatives further include heteroalkyl derivatives of the alkyl portion of the lower chain alkyl and aralkyl moieties, including (but not limited to) alkyl and aralkyl phosphonates and silanes.
- R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 9 moieties specifically include (but are not limited to) —OH, —OR, —COR, —COOR, —CONH 2 , —CONR, —CONRR, —NH 2 , —NHR, —NRR, —SO 2 R and —COSR, wherein each occurrence of R is as defined above.
- R 1 , R 2 , R 5 , R 6 , R 7 , R 8 or R 9 may be a linker facilitating the linkage of the compound to another moiety or compound.
- the compounds for use in this invention may be linked to one or more known compounds, such as biotin, for use in diagnostic or screening assay.
- R 1 , R 2 , R 5 , R 6 , R 7 , R 8 or R 9 may be a linker joining the compound to a solid support (such as a support used in solid phase peptide synthesis) or alternatively, may be the support itself.
- linkage to another moiety or compound, or to a solid support is preferable at the R 1 , R 2 , R 7 or R 8 position, and more preferably at the R 1 or R 2 position.
- R 1 , R 2 , R 4 , R 6 , R 9 , W and X are as defined above, Z is nitrogen or CH (when Z is CH, then X is nitrogen).
- R 1 , R 2 , R 6 , and R 9 represent the remainder of the compound, and R 4 is selected from an amino acid side chain moiety.
- A is —O—CHR 3 —
- B is —NR 4 —
- D is —(C ⁇ O)—
- E is —(ZR 6 )—
- Gi is (XR 7 ) n —
- the ⁇ -helix mimetic compounds for use in this invention have the following formula (IV):
- R 1 , R 2 , R 4 , R 6 , R 7 , W, X and n are as defined above, and Z is nitrogen or CH (when Z is nitrogen, then n is zero, and when Z is CH, then X is nitrogen and n is not zero).
- R 1 , R 2 , R 6 , and R 7 represent the remainder of the compound, and R 4 is selected from an amino acid side chain moiety.
- R 6 or R 7 may be selected from an amino acid side chain moiety when Z and X are CH, respectively.
- the ⁇ -helix mimetic structures for use in the present invention may be prepared by utilizing appropriate starting component molecules (herinafter referred to as “component pieces”). Briefly, in the synthesis of ⁇ -helix mimetic structures having formula (II), first and second component pieces are coupled to form a combined first-second intermediate, if necessary, third and/or fourth component pieces are coupled to form a combined third-fourth intermediate (or, if commercially available, a single third intermediate may be used), the combined first-second intermediate and third-fourth intermediate (or third intermediate) are then coupled to provide a first-second-third-fourth intermediate (or first-second-third intermediate) which is cyclized to yield the ⁇ -helix mimetic structures of this invention.
- the ⁇ -helix mimetic structures of formula (II) may be prepared by sequential coupling of the individual component pieces either stepwise in solution or by solid phase synthesis as commonly practiced in solid phase peptide synthesis.
- a “first component piece” has the following formula S1
- R 2 as defined above, and R is a protective group suitable for use in peptide synthesis.
- Suitable R groups include alkyl groups and, in a preferred embodiment, R is a methyl group.
- Such first component pieces may be readily synthesized by reductive amination or substitution reaction by displacement of H 2 N—R 2 from CH(OR) 2 —CHO or CH(OR) 2 —CH 2 -Hal (wherein Hal means a halogen atom).
- a “second component piece” has the following formula S2:
- L1 is carboxyl-activation group such as halogen atom
- R 3 , R 4 is as defined above
- P is an amino protective group suitable for use in peptide synthesis.
- Preferred protective groups include t-butyl dimethylsilyl (TBDMS), t-Butyloxycarbonyl (BOC), Methylosycarbonyl (MOC), 9H-Fluorenylmethyloxycarbonyl (FMOC), and allyloxycarbonyl (Alloc).
- TDMS t-butyl dimethylsilyl
- BOC t-Butyloxycarbonyl
- MOC Methylosycarbonyl
- FMOC 9H-Fluorenylmethyloxycarbonyl
- Alloc allyloxycarbonyl
- L is —C(O)NHR
- —NHR may be an carboxyl protective group.
- N-hydrazino amino acids can be readily prepared according to the procedures of Vidal et al.
- Suitable activated carboxylic acid groups include acid halides where X is a halide such as chloride or bromide, acid anhydrides where X is an acyl group such as acetyl, reactive esters such as an N-hydroxysuccinimide esters and pentafluorophenyl esters, and other activated intermediates such as the active intermediate formed in a coupling reaction using a carbodiimide such as dicyclohexylcarbodiimide (DCC).
- X is a halide such as chloride or bromide
- X is an acyl group such as acetyl
- reactive esters such as an N-hydroxysuccinimide esters and pentafluorophenyl esters
- other activated intermediates such as the active intermediate formed in a coupling reaction using a carbodiimide such as dicyclohexylcarbodiimide (DCC).
- DCC dicyclohexylcarbodiimide
- a “third component piece” has the following formula S3:
- Suitable third component pieces are commercially available from a variety of sources or can be prepared by known methods in organic chemistry.
- the ⁇ -helix mimetic structures for use in this invention of formula (II) are synthesized by reacting a first component piece with a second component piece to yield a combined first-second intermediate, followed by either reacting the combined first-second intermediate with third component pieces sequentially to provide a combined first-second-third-fourth intermediate, and the cyclizing this intermediate to yield the ⁇ -helix mimetic structure.
- a first component piece 1 is coupled with a second component piece 2 by using coupling reagent such as phosgene to yield, after N-deprotection, a combined first-second intermediate 1-2 as illustrated below:
- R 1 , R 2 , R 4 , R 7 .Fmoc, Moc and X are as defined above, and Pol represents a polymeric support.
Abstract
Description
-
- Given the enormous potential of stem cells to the development of new therapies for the most devastating diseases, when a readily available source of stem cells is identified, it is not too unrealistic to say that this research will revolutionize the practice of medicine and improve the quality and length of life (National Institutes of Health. Stem Cells: Scientific Progress and Future Research Directions. Jun. 17, 2001.). However, the development of such applications for adult stem cells has been severely impaired due to the inability to propagate and expand functional adult stem cells in culture. To date, this has proven to be a singular challenge in stem cell research (Sherley, J. (2002) Stem Cells, 20:561-572). For decades, scientists have attempted to grow stem cells in culture to increase the number of cells for transplantation. The challenge of this undertaking lies in the stem cell's predisposition to differentiate. This problem may be associated with the inherent asymmetric cell kinetics of stem cells in postnatal somatic tissues (Sherley, J. (2002) Stem Cells, 20:561-572). Existing scientific methods used for increasing the number of stem cells include culturing cells on 2-D stromal layers and growing them in the presence of various cytokine cocktails (Rebel, V I., et al. (1994) Blood, 83(1):128-136). However, none of the existing ex vivo methods can prevent differentiation of stem cells while promoting proliferation (Rebel, V I. et al. (1996) J Hematother. 5(1):25-37). There is therefore a need in the art for compounds and methods for use in propagating and expanding adult stem cells in culture.
-
- wherein A is —(CHR3)—(C═O)—. B is —(NR4)—, D is —(CHR5)— or —(C═O)—, E is —(ZR6)—, —(C═O)—, G is —(XR7)n—, —(CHR7)—(NR8)—, —(C═O)—(XR9)—, or —(C═O)—, W is —Y(C═O)—, —(C═O)NH—, —(SO2)— or nothing, Y is oxygen or sulfur, X and Z is independently nitrogen or CH, n=o or 1; and R1, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are the same or different and independently selected from an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers thereof. R2 is selected from a monocyclic aryl or heteroaryl moiety bearing the substituent NR10R11, wherein the compound binds preferentially to p300 phosphorylated at Ser89.
wherein A is —(C═O)—(CHR3)—, B is —N—R4—, D is —(CHR5)— or —(C═O)—, E is —(ZR6)— or —(C═O)—, G is —(XR7)n—, —(CHR7)—(NR8)—, —(C═O)—(XR9)—, or —(C═O)—, W is —Y(C═O)—, —(C═O)NH—, —(SO2)— or nothing, Y is oxygen or sulfur, X and Z is independently nitrogen or CH, n=0 or 1; and R1, R2, R3, R4, R5, R6, R7, R8 and R9, are the same or different and independently selected from an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers thereof.
TABLE 1 |
Amino Acid Side Chain Moieties |
Amino Acid Side Chain Moiety | Amino Acid | ||
—H | Glycine | ||
—CH3 | Alanine | ||
—CH(CH3)2 | Valine | ||
—CH2CH(CH3)2 | Leucine | ||
—CH(CH3)CH2CH3 | Isoleucine | ||
—(CH2)4NH3 + | Lysine | ||
—(CH2)3NHC(NH2)NH2 + | Arginine | ||
Histidine | |||
—CH2COO− | Aspartic acid | ||
—CH2CH2COO− | Glutamic acid | ||
—CH2CONH2 | Asparagine | ||
—CH2CH2CONH2 | Glutamine | ||
Phenylalanine | |||
Tyrosine | |||
Tryptophan | |||
—CH2SH | Cysteine | ||
—CH2CH2SCH3 | Methionine | ||
—CH2OH | Serine | ||
—CH(OH)CH3 | Threonine | ||
Proline | |||
Hydroxyproline | |||
wherein R1, R2, R4, R6, R9, W and X are as defined above, Z is nitrogen or CH (when Z is CH, then X is nitrogen). In a preferred embodiment, R1, R2, R6, and R9 represent the remainder of the compound, and R4 is selected from an amino acid side chain moiety. In a more specific embodiment wherein A is —O—CHR3—, B is —NR4—, D is —(C═O)—, E is —(ZR6)—, Gi is (XR7)n—, the α-helix mimetic compounds for use in this invention have the following formula (IV):
wherein R1, R2, R4, R6, R7, W, X and n are as defined above, and Z is nitrogen or CH (when Z is nitrogen, then n is zero, and when Z is CH, then X is nitrogen and n is not zero). In a preferred embodiment, R1, R2, R6, and R7 represent the remainder of the compound, and R4 is selected from an amino acid side chain moiety. In this case, R6 or R7 may be selected from an amino acid side chain moiety when Z and X are CH, respectively.
Wherein R2 as defined above, and R is a protective group suitable for use in peptide synthesis. Suitable R groups include alkyl groups and, in a preferred embodiment, R is a methyl group. Such first component pieces may be readily synthesized by reductive amination or substitution reaction by displacement of H2N—R2 from CH(OR)2—CHO or CH(OR)2—CH2-Hal (wherein Hal means a halogen atom).
Where L1 is carboxyl-activation group such as halogen atom, R3, R4 is as defined above, and P is an amino protective group suitable for use in peptide synthesis. Preferred protective groups include t-butyl dimethylsilyl (TBDMS), t-Butyloxycarbonyl (BOC), Methylosycarbonyl (MOC), 9H-Fluorenylmethyloxycarbonyl (FMOC), and allyloxycarbonyl (Alloc). When L is —C(O)NHR, —NHR may be an carboxyl protective group. N-hydrazino amino acids can be readily prepared according to the procedures of Vidal et al. (Tetrahedron Letters 39:8845-8848, 1998). The conversion of these compounds to the second component pieces of this invention may be readily achieved by activation of the carboxylic acid group of the N-protected hydrazino-amino acid. The conversion of these compounds to the second component pieces may be readily achieved by activation of the carboxylic acid group of the N-protected hydrazino-amino acid. Suitable activated carboxylic acid groups include acid halides where X is a halide such as chloride or bromide, acid anhydrides where X is an acyl group such as acetyl, reactive esters such as an N-hydroxysuccinimide esters and pentafluorophenyl esters, and other activated intermediates such as the active intermediate formed in a coupling reaction using a carbodiimide such as dicyclohexylcarbodiimide (DCC).
where G, E, and L1 are as defined above. Suitable third component pieces are commercially available from a variety of sources or can be prepared by known methods in organic chemistry.
wherein R1, R2, R4, R7.Fmoc, Moc and X are as defined above, and Pol represents a polymeric support.
Claims (8)
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